Reducing Disease And Disability

Chronic disease and disability can compromise the quality of life for older people. Some 79 percent of people age 70 and older have at least one of seven potentially disabling chronic conditions (arthritis, hypertension, heart disease, diabetes, respiratory diseases, stroke, and cancer).6 The burden of such chronic conditions is felt not only by individuals but also by families, employers, and the health care system. Research to improve understanding of the risk and protective factors for chronic disease and disability can lead to the development of effective prevention strategies.

Treatment and Prevention of Disease

Treatment of any specific disease in older people can be complicated by the presence of other diseases and disorders and by the concomitant use of multiple medications to treat various conditions. Potential interactions of medications, including those of prescribed drugs with over-the-counter drugs and dietary supplements, represent additional concerns. Moreover, adherence to treatment regimens can be difficult, as older patients often must maintain a complex medication schedule. Research is ongoing to determine the best treatment approaches for older patients, particularly those with concurrent medical conditions, and to identify strategies for improving adherence and minimizing potentially adverse effects of medications.

Newly defined pathway for steroid action on cells provides the means to reverse osteoporosis in mice. It is estimated that over 10 million men and women currently have osteoporosis and an additional 18 million have low bone mass and are at risk.7 Treatment options for women have most often included hormone replacement therapy involving estrogen; however, recent clinical evidence has indicated that estrogen replacement therapy may have undesired side effects on other organs.

Investigators have outlined a previously unrecognized pathway for estrogen action through a receptor at the cell surface, with subsequent steps to influence a set of genes in the nucleus that had not been known to be involved with estrogen action. In addition, they found that this pathway of action is also used by androgen receptors and that a synthetic compound, 4-estren-3a, 17ß-diol, can activate both estrogen and androgen receptor pathways. Finally, studies in both male and female mice demonstrate that this mechanism of action by estren can be used not only to preserve bone in animals lacking estrogen, but also to increase bone mass without stimulating unwanted effects in reproductive organs. This work has already had far-reaching effects in bone and steroid biology and provides an entirely new pathway for future clinical investigation to not only stop progression of bone loss, but reverse bone loss without dangerous side effects.

Mimicking caloric restriction to increase longevity in animal models. Reducing calorie intake increases longevity and delays adverse age-related changes in a variety of organisms. However, the mechanism whereby caloric restriction works remains unknown, thus preventing rational development of biological interventions to produce the effect provided by actually restricting calories. Several recently discovered genetic and pharmacological interventions are providing clues about ways to mimic caloric restriction, and are indirectly leading to a better understanding of the mechanism of caloric restriction. For example:

Researchers have identified a fruit fly gene called Indy (“I’m not dead yet”), which, when mutated, doubles the life span of the fly without apparent ill effects. The normal Indy gene is involved in the transport of certain nutrients between cells; when mutated, this transport is dramatically slowed, delivery of the nutrients to the cells is restricted, and overall energy metabolism is reduced.

Studies in yeast provide another perspective on the mechanism of caloric restriction. Investigators have found that several compounds that increase activity of the enzyme sir2 in yeast also increase their mean longevity. The most potent activator of sir2 identified so far is resveratrol, a compound found in many foods, especially red wine. The investigators postulate that sir2 expression and activity mimic the mild stress induced in yeast by caloric restriction. The possible benefits of resveratrol in the human diet have been noted previously, but the mechanism of its beneficial actions was not known.

Intensity of warfarin therapy affects stroke severity and mortality in older patients with atrial fibrillation. Atrial fibrillation (AF) is a disorder of heart rhythm whose frequency increases greatly with advancing age. Research has shown that the incidence of ischemic stroke (stroke caused by blood clots) among older patients with AF is greatly reduced by treatment with warfarin, a drug used to control and prevent blood clotting disorders. This therapy helps maintain an International Normalized Ratio (INR) (an index of anticoagulation intensity) value of 2.0 or greater. However, warfarin’s effect on the severity of stroke and stroke-related mortality is less well known. Researchers examined ischemic stroke outcomes in a large group of older patients with AF. They found that patients who received anticoagulation therapy resulting in an INR value of 2.0 or greater at the time of stroke were likely to have less severe neurologic damage than patients who did not receive anticoagulation therapy, or who received therapy that resulted in an INR value of less than 2.0. Further, the 30-day mortality rate was significantly lower in patients who received warfarin resulting in an INR value of 2.0 or greater, compared with the mortality rate in patients who received warfarin resulting in an INR value of less than 2.0. Older individuals with AF are often treated less aggressively due to concern over possible adverse effects, but these findings emphasize the importance of maintaining adequate anticoagulation in this population.

Advances in the diagnosis and treatment of prion diseases. Prions are infectious proteins that transform a normal cellular protein (PrPC) into an abnormal virulent form (PrPSc) that accumulates in the central nervous system, producing fatal neurological disease characterized by sponge-like holes in the brain that result in progressive disturbances in movement, emotion, sleep, and cognition. Recent research has targeted the diagnosis and treatment of prion diseases. Commercially viable and automated diagnostic tests for bovine spongiform encephalopathy (BSE, or “mad cow disease”) and chronic wasting disease (CWD), a wildlife disease in North America, have recently been developed; the sensitivity of these new tests is at least 10 times greater than conventional bioassay methods for BSE and CWD. Investigators have also developed a series of derivatives of the anti-malarial drug quinacrine, which is currently under clinical evaluation for treatment of prion diseases. These compounds, which were engineered for increased potency, were both empirically tested and computer modeled to explore the maximal clearance of PrPSc from cells in tissue culture while minimizing cellular toxicity. Several compounds that were at least 10 times more effective than quinacrine were identified; these compounds may prove potent alternatives to quinacrine treatment.

Exendin-4 as a treatment for type 2 diabetes. NIH investigators searching for potential treatments for type 2 diabetes conducted a study of the compound exendin-4. This compound is an analog of the gut hormone GLP-1, which is naturally released after eating and which can lower blood sugar in people with diabetes when given in sufficient doses. Study participants received injections of the drug twice daily for a month. The investigators found that: 1) exendin-4 is well tolerated, 2) it retains efficacy for at least one month, 3) there were no unexpected side effects, and 4) it is at least as effective in lowering blood glucose as current treatments for type 2 diabetes. These results indicate that exendin 4-is a viable potential candidate agent for treating type 2 diabetes, and that phase 3 studies of the drug are appropriate.Story of Discovery: Multipotent Stem Cells and the Diseases of Aging diabetes, and that phase 3 studies of the drug are appropriate.

Story of Discovery: Multipotent Stem Cells and the Diseases of Aging

As we grow older, we become increasingly vulnerable to the development of many age-related chronic conditions, including Alzheimer’s disease, Parkinson’s disease, heart disease, and diabetes. These conditions, which are characterized by damage to and death of cells in various organs and systems, impair quality of life and are frequently fatal. However, we carry within ourselves the seeds of our own cellular renewal in the form of primitive cells, called stem cells, that have the potential to repair damaged tissue. Although stem cells appear to be present in numbers or in functional capacity that is insufficient to effectively combat some of the diseases of aging unaided, new research findings are suggesting ways to harness the power of these remarkable cells to treat a number of diseases and conditions.

A particularly exciting area of stem cell research is in “adult” stem cells. Adult stem cells have not yet differentiated into cells of a particular type (e.g., neural cells, blood cells, etc.), but they may be committed to doing so. For example, in the bone marrow, some stem cells give rise to red blood cells, white blood cells, and platelets, while others make bone cells and may be able to make additional cell types under appropriate conditions.

Researchers have known about stem cells since around the turn of the twentieth century, when European scientists made the momentous discovery that all blood cells derive from a single type of primitive cell. But it wasn’t until 1961 that researchers identified the properties of the hematopoietic stem cell B a groundbreaking finding that led to the development and refinement of the bone marrow transplant, which is today a widely-adopted treatment for certain types of leukemia and other blood diseases.

Today, stem cells have been identified in tissues throughout the body, including the blood, the brain, the liver, the skin, and even the teeth, and new information is rapidly emerging about the properties of stem cells and their potential uses. For example, NIH-supported researchers recently identified, for the first time, a population of stem cells in the heart, and this finding provided important information about the underlying pathology of the diseased heart. Examining heart muscle tissue from older individuals with and without heart disease, they found that, in the normal heart, myocytes (the cells of the heart muscle) may lose their ability to replicate, but are replaced by cardiac stem cells. In the diseased heart, the stem cells do not adequately replace the lost myocytes, leading to an imbalance between cell death and regeneration that is associated with the development of pathology. The identification of cardiac stem cells suggests new avenues for myocardial repair, and provides important information about the pathogenesis of heart disease and failure.

Neural stem cells are of particular interest to the study of Alzheimer’s disease and other neurodegenerative diseases of aging. Through several recent studies, NIH-supported researchers have found that environmental cues, which vary among brain subregions, may determine the fate of a stem cell, that neurogenesis (or the formation of new neurons) may require the cooperation of multiple protein factors, and that neural stem-like cells from human brain tissue can form neurons.

In fact, several recent studies demonstrate that neural stem cells in the adult hippocampus, a brain area important for learning and memory, develop essential properties of functional neurons. The new neurons have properties similar to their mature neighbors; they receive input from other cells; they make functional connections, called synapses, with normal hippocampal neurons; and they release neurotransmitters, the chemical mediators of neuronal communication. Moreover, new neurons are made in the aged brain, and a recent study showed that once new neurons find a home in the hippocampus, they remain stable in numbers and location over time.

Whether adult stem cells from different sources can form several cell types, or can best replace cells of a particular type, they have enormous potential for cell-based therapies in disease. Clinical and preclinical research in this area is ongoing. In one recent, highly provocative study, mice in which heart damage had been induced were injected with cytokines (proteins) called stem cell factor (SCF) and granulocyte-colony-stimulating factor (G-CSF). Stimulated by the cytokines, primitive bone marrow cells swarmed to the hearts, converted to several different types of cardiac cells, and contributed to repair of the damaged tissue, improving both the heart function and the survival of the treated mice. This finding, while preliminary, suggests that it may be possible to mobilize the body’s own naturally-occurring stem cells to repair tissue damage and fight disease. Other potential applications include replacing dopamine-producing cells in the brains of Parkinson’s disease patients or developing insulin-producing cells for type I diabetes. Although there is currently no widespread clinical application of such treatments, the use of stem cells to combat the diseases of aging may be just around the corner.

Molecular Understanding of Disease Processes

Gene expression profiling in Werner’s Syndrome (WS) closely resembles that of normal aging. WS is a condition in which younger patients display a number of the clinical signs and symptoms usually associated with normal aging. To assess whether WS features are related to the same genetic influences as normal aging, investigators characterized the expression of 6,912 genes derived from young donors, old donors, and WS patients. Of the analyzed genes, 6.3 percent displayed significant differences in expression when either WS or old donor cells were compared to young donor cells. Expression alterations in WS were also strikingly similar to those in normal aging. These results suggest that a difference in the expression of certain genes could produce many of the complex clinical features of WS. The remarkable similarity between WS and normal aging suggests that WS is associated with the acceleration of a normal aging mechanism. This supports the use of WS as an aging model, and identifies genes that may be important in aging.

“Fat Genes” in the worm may shed light on human obesity. Data from the Centers for Disease Control indicate that among U.S. adults ages 20-74, 35 percent are overweight (defined as having a body mass index, or BMI, of 25.0-29.9), and some 27 percent are clinically obese (BMI is 30.0 or above).8 Overweight and obesity are associated with an array of health problems, including heart disease, stroke, osteoarthritis, adult-onset diabetes, and certain types of cancer. Although behavioral and environmental factors are the primary contributors to overweight and obesity, heredity plays a significant role in determining individual susceptibility to these conditions, and genes influence how the body burns calories for energy and stores fat. NIH-supported researchers recently searched for genes necessary for fat storage in C. elegans, a tiny worm that is frequently used in genetic studies. Using RNA interference (RNAi), a technique in which genes are inactivated one at a time to determine their function, the investigators screened the 16,757 genes in the C. elegans genome and found 417 genes involved in fat storage. Inactivation of 305 genes caused reduced body fat, and inactivation of 112 genes increased fat storage. Many of these C. elegans fat regulatory genes have human counterparts, a number of which have not been previously implicated in the regulation of fat storage. The fat regulation genes identified in C. elegans may suggest new targets for treating human obesity and its associated diseases.

Age-associated alternations in mitochondrial function are implicated in insulin resistance in older persons. Insulin resistance is a metabolic disorder that can occur with advancing age and is thought to precede the development of type II diabetes in older adults. The underlying disease process of type II diabetes among older persons is not yet known. However, researchers hypothesize that age-related increases in the fat content of muscle may play an important role in the development of insulin resistance, and that age-related changes in the function of mitochondria (the cells’ “energy centers”) may be responsible for this accumulation. In a recent study, investigators used nuclear magnetic resonance (NMR) spectroscopy, a technology that allows non-invasive quantification of fat content in tissues and can also measure muscle metabolism, to determine whether insulin resistance in older persons is associated with increased fat content within muscle. The participants consisted of healthy older and young individuals who were matched by their muscle mass and body fat content. The older study participants were significantly insulin-resistant compared to the young, mainly due to increased muscle insulin resistance. NMR spectroscopy data revealed increased fat content and reduced mitochondrial activity in muscle. These results indicate an association between altered mitochondrial function in humans and an accumulation of fat within muscle that in turn leads to insulin resistance.